Abstract
Background: Chronic myeloid leukemia (CML) risks may equal the number of hematopoietic stem cells (HSC) per person N multiplied by the risk per HSC. If N is regulated to increase only if below a threshold needed to sustain a functional hematopoietic system, N would then lie in a dead-band of acceptable values [Radiat Res157 106-109 (2002)] that may have evolved to be not too high to avoid hematologic malignancy risks and not too low to have sufficient reserves in times of severe needs. This view is consistent with broad variation in N across individuals, low N after marrow transplants, and N varying across races and cities. If N can be manipulated, perhaps via TET2 activity, monitoring and controlling N could become an important public health objective. Our goal is to estimate N by combining CML incidence data with BCR and ABL data.
Methods: Using intron and genome sizes we estimated N by analyzing CML incidence and translocations as functions of radiation dose [Math Biosci162, 85-101 (1999)] and age [Radiat Environ Biophys38, 201-206 (1999)]. As CML risk is fixed by epidemiological data, increases in risks per cell due to BCR-to-ABL tethering [Chromosoma108, 426-435 (1999)] imply lower estimates of N [Radiat Environ Biophys40, 1-9 (2001)]. Assuming such tethering, and sex differences in CML incidence being due to N rather than latency [Radiat Environ Biophys53, 55-63 (2014)], fitting Eq. (1) to A-bomb survivor data yields, via Eqs. (2) and (3), city- and sex specific A-bomb survivor estimates of N (Table 1). In Eq. (1), the first term is the background incidence, the second the probability of radiation forming BCR-ABL in any of N HSC per person and observing CML t years later, and the third the probability of HSC survival; consistent with a dead-band this probability also multiplies the background incidence. Eqs. (2) and (3) show how fitted parameters of the radiation induced term and an external estimate of the risk per cell r were merged to estimate N. To identify chemotherapy-associated reductions in radiation-induced CML risks in Surveillance, Epidemiology, and End Results (SEER) data (Figure 1) we used our R package SEERaBomb [Leukemia30, 285-94 (2016)].
Results: A-bomb survivor data yields estimates of N that are lower in females and lower in Nagasaki (Table 1). Perhaps related to low Nagasaki rates, in SEER patients irradiated for a previous cancer, CML risks are lower in those also treated with chemotherapy (Figure 1).
Discussion: It is not known why CML incidence is lower in Nagasaki. Environmental exposures in Nagasaki not present in Hiroshima may have lowered N within the HSC dead-band, either via direct HSC killing or via HSC exhaustion as a result of high downstream cell turnover. For HSC killing as the mechanism, as most HSC are quiescent and thus in G0/G1 wherein error-prone non-homologous end-joining DNA double strand break repair is dominant, suspects include agents that cause cell-lethal DNA double-strand break misrejoinings, such as large deletions and dicentrics. Nagasaki survivors had greater gamma vs. neutron exposures due to plutonium vs. uranium bomb differences, and for a fixed dose, this decreases the probability of killing a struck HSC while increasing the probability of an HSC being struck. Neutron doses were, however, a small fraction of total doses. Another option is a chemical exposure. Chemotherapy reducing radiation-induced CML in Figure 1 suggests that differences in city industries should be considered. For HSC exhaustion as a mechanism of lowering N, if pregnancies reduce breast cancer risks by consuming target cells, a chronic infection could in principle also shift N down in the dead-band. HTLV in Nagasaki but not Hiroshima is not suspected, but perhaps it should be. Radiation does not induce adult T-cell leukemia (ATL), but HTLV lowering N in most people infected might be independent of it causing ATL in a few, and N stopping at the dead-band threshold implies that HTLV is not expected to cause anemia, and it does not.
If values of N in the dead-band evolved to be high to survive young adult ages in a more violent non-hygienic world, lowering N, as Nagasaki survivors may have proven is possible, may be a worthwhile goal. CML incidence could be a reporter of N and thus a means of monitoring it. If the target cells of chronic lymphocytic leukemia (CLL) are also HSC, and lower rates of CLL in Nagasaki survivors reflect lower N, lowering N could become an important means of preventing chronic leukemias.
Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy.
